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Access hsTnI is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of cardiac troponin I (cTnI) levels in human serum and plasma using the Unicel DxI Immunoassay Systems to aid in the diagnosis of myocardial infarction (MI).

The Access hsTnI is a two–site immunoenzymatic ("sandwich") assay. Monoclonal anti–cTnI antibody conjugated to alkaline phosphatase is added to a reaction vessel along with a surfactant–containing buffer and sample. After a short incubation, paramagnetic particles coated with monoclonal anti–cTnI antibody are added. The human cTnI binds to the anti–cTnI antibody on the solid phase, while the anti–cTnI antibody–alkaline phosphatase conjugate reacts with different antigenic sites on the cTnI molecules. After incubation, materials bound to the solid phase are held in a magnetic field while unbound materials are washed away. Then, the chemiluminescent substrate is added to the vessel and light generated by the reaction is measured with a luminometer. The light production is directly proportional to the concentration of analyte in the sample. Analyte concentration is automatically determined from a stored calibration.

Here's a breakdown of the acceptance criteria and study information for the Access hsTnI device, based on the provided FDA 510(k) clearance letter:

Acceptance Criteria and Reported Device Performance

Study Details

The provided document describes a study primarily focused on demonstrating the substantial equivalence of the Access hsTnI assay when run on the UniCel DxI 800 Immunoassay System compared to its predicate device (Access hsTnI on the Access 2 Immunoassay System). This is achieved through performance testing of various analytical aspects.

1. Sample Size Used for the Test Set and Data Provenance:

   • Method Comparison: 239 samples (119 Lithium Heparin Plasma and 120 Serum).
   • Data Provenance: Not specified (e.g., country of origin). The document indicates it's a retrospective comparison between the "IVD Access hsTnI (Current Assay Protocol File (APF))" and the "proposed Access hsTnI (Proposed APF)" on the UniCel DxI 800 instruments, implying existing samples or previously collected data.

2. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts:

   • Not Applicable. This device is an in-vitro diagnostic (IVD) immunoassay for quantitative determination of cTnI levels. The "ground truth" for the test set in this context refers to the measured cTnI values, which are inherently quantitative and determined by the predicate device's method and the proposed device's method, not by expert consensus or interpretation of images/clinical findings.

3. Adjudication Method for the Test Set:

   • Not Applicable. As noted above, this is a quantitative analytical method comparison, not a diagnostic interpretation or clinical outcome study that would require adjudication.

4. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, If So, What Was the Effect Size of How Much Human Readers Improve with AI vs Without AI Assistance:

   • Not Applicable. This is an in-vitro diagnostic device, not an AI-based image interpretation or diagnostic aid system involving human readers.

5. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done:

   • Yes, implicitly. The studies described (Method Comparison, Imprecision, Linearity, LoB/LoD, LoQ, Carryover) evaluate the performance of the analytical instrument and assay without human intervention in the measurement process. The device itself is an automated immunoassay system that produces quantitative results.

6. The Type of Ground Truth Used:

   • The "ground truth" in this context refers to the quantitative measurements of cTnI levels themselves. For the method comparison, the predicate device (Access hsTnI on the Access 2 Immunoassay System, or the "Current Assay Protocol File (APF)" on the DxI 800) essentially serves as the reference for comparison against the "Proposed APF" on the UniCel DxI 800. Therefore, it's a comparison against an established, legally marketed reference measurement method.

7. The Sample Size for the Training Set:

   • Not specified. This documentation primarily focuses on the validation of the device's analytical performance. While there would have been internal development and optimization (which could be considered "training"), the document does not distinguish a formal "training set" (as might be seen with AI/ML models) from "internal validation" data. The tested datasets described are for analytical validation.

8. How the Ground Truth for the Training Set Was Established:

   • Not specified / Not applicable in the traditional sense. As an IVD assay, the "ground truth" for developing such a test is the accurate quantitative measurement of the analyte (cTnI) in biological samples, requiring highly controlled reference methods and materials. The document indicates the device's principle is a "two-site immunoenzymatic ('sandwich') assay," which is a well-established biochemical technique. The development process would involve extensive characterization against reference standards and known concentrations, rather than establishing ground truth through, for example, expert labeling of clinical data.

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Access hsTnI is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of cardiac troponin I (cTnI) levels in human serum and plasma using the Access 2 Immunoassay Analyzers to aid in the diagnosis of myocardial infarction (MI).

The Access hsTnI assay is a two–site immunoenzymatic ("sandwich") assay. Monoclonal anti–cTnI antibody conjugated to alkaline phosphatase is added to a reaction vessel along with a surfactant–containing buffer and sample. After a short incubation, paramagnetic particles coated with monoclonal anti–cTnI antibody are added. The human cTnI binds to the anti–cTnI antibody on the solid phase, while the anti–cTnI antibody–alkaline phosphatase conjugate reacts with different antigenic sites on the cTnI molecules. After incubation, materials bound to the solid phase are held in a magnetic field while unbound materials are washed away. Then, the chemiluminescent substrate is added to the vessel and light generated by the reaction is measured with a luminometer. The light production is directly proportional to the concentration of analyte in the sample. Analyte concentration is automatically determined from a stored calibration.

The provided text describes the 510(k) clearance for the Beckman Coulter Access hsTnI device, specifically focusing on demonstrating its equivalence when run on the DxC 500i Clinical Analyzer compared to the previously cleared Access 2 Immunoassay System. The "acceptance criteria" and "study that proves the device meets the acceptance criteria" in this context refer to the analytical performance characteristics required to show substantial equivalence between the new platform (DxC 500i) and the cleared predicate platform (Access 2) for the Access hsTnI assay.

Here's a breakdown of the requested information based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

Note: The acceptance criteria for the "Platform Equivalency" and "Clinical Performance" studies are largely the same (slope 1.00 ± 0.10 and r ≥ 0.90), indicating the central intent was to show the DxC 500i performs equivalently to the Access 2 for this assay.

2. Sample Size Used for the Test Set and Data Provenance

• Platform Equivalency Study (Method Comparison - Representative) Sample Size:
  • Serum: N = 106
  • Plasma: N = 122
• Clinical Performance (Method Comparison) Sample Size:
  • "More than 200 discrete lithium heparin plasma samples" per site for a total of three sites (2 external, 1 internal). This implies a total sample size of >600 for this specific study.
• Imprecision, Linearity, Detection Capability, and Carryover studies: Sample sizes are not explicitly stated for these, but they are implied to be sufficient for the CLSI standards cited (EP05-A3, EP06-2nd Edition, EP17-A2).
• Data Provenance: The studies were conducted at "two external tests sites and one internal test site." The specific country of origin is not mentioned, but "Beckman Coulter, Inc." is based in California, USA. The data is prospective as it involves controlled studies and analyses to demonstrate performance on the new platform.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications

This section is Not Applicable to this device. The Access hsTnI assay is an in vitro diagnostic (IVD) test that quantitatively measures a biomarker (cardiac troponin I). The "ground truth" for method comparison and analytical performance studies of IVDs is typically established by comparative analysis against a reference method or a legally marketed predicate device, as seen here. It does not involve human expert interpretation of images or signals that would require expert consensus for ground truth.

4. Adjudication Method for the Test Set

This section is Not Applicable. As stated above, this is an IVD device for quantitative measurement. The "test set" in this context refers to patient samples with varying concentrations of the analyte, measured by both the candidate and predicate devices. There is no human interpretation or subjective assessment that would require adjudication.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

This section is Not Applicable. The device is a quantitative immunoassay, not an AI-powered diagnostic imaging or interpretation tool that assists human readers. Therefore, an MRMC study is not relevant.

6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was done

This section is Not Applicable in the context of an "algorithm only" being evaluated for standalone performance. The Access hsTnI device on the DxC 500i is a laboratory instrument system performing a chemical assay. Its "performance" is inherently "standalone" in the sense that the instrument provides a quantitative result without immediate human-in-the-loop assistance for that specific measurement. The "comparison testing" essentially evaluates its standalone performance against a predicate standalone device.

7. The Type of Ground Truth Used

The "ground truth" for the test set was essentially:

• Measurement by the legally marketed predicate device (Access hsTnI on Access 2 Immunoassay System): This is the gold standard against which the performance of the Access hsTnI on the DxC 500i Clinical Analyzer is compared to demonstrate substantial equivalence.
• Definitions within CLSI guidelines: For parameters like precision, linearity, and detection capability, the "ground truth" is adherence to statistical and analytical performance models defined by the specified CLSI (Clinical and Laboratory Standards Institute) guidelines.

8. The Sample Size for the Training Set

This section is Not Applicable. The Access hsTnI is a reagent and instrument system for an immunoassay. It is not an AI/ML algorithm that requires "training data" in the typical sense. The term "training set" is usually associated with machine learning models. The development and validation of such IVD assays involve extensive R&D, method development, and verification on an internal set of samples, but these are not referred to as a "training set" in the context of AI.

9. How the Ground Truth for the Training Set was Established

This section is Not Applicable for the reasons stated in point 8.

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The i-STAT hs-Tnl cartridge with the i-STAT 1 System is in the in vitro quantification of cardiac troponin I (cTnl) in whole blood or plasma samples in point of care or clinical laboratory settings.

The i-STAT hs-Tnl cartridge with the i-STAT 1 System is intended to be used as an aid in the diagnosis of myocardial infarction (MI).

The i-STAT hs-TnI cartridge is an in vitro diagnostic test for the quantitative measurement of cardiac troponin I (cTnI) in whole blood or plasma samples using the i-STAT 1 analyzer in point of care or clinical laboratory settings.

The i-STAT hs-TnI test uses an enzyme-linked immunosorbent assay (ELISA) method with electrochemical detection of the resulting enzyme signal. The test reports a quantitative measurement of the sample concentration of cTnI in units of ng/L in approximately 15 minutes.

The i-STAT hs-TnI immunoassay test method uses anti-cTnI antibodies for labeling and capture. The capture antibodies are coated on para-magnetic microparticles. Both label and capture antibodies are contained within the cartridge on a biosensor chip. The ELISA is initiated when the test cartridge is inserted into the analyzer. The sample is positioned over the biosensor chip to dissolve the reagents. This forms the ELISA sandwich (detection antibodylabel/antigen/capture antibody). The sample and excess antibody-conjugate are then washed off the sensors. An enzyme within the ELISA sandwich generates an electrochemically detectable product. The biosensor chip measures the enzyme product which is proportional to the concentration of cTnI within the sample.

The i-STAT hs-TnI cartridge is a single use test cartridge. The cartridge contains a biosensor chip and all reagents required to execute the test cycle. All fluid movements within the cartridge (test sample or reagent) are automatically controlled by the i-STAT 1 analyzer by electromechanical interaction with the cartridge. The analyzer executes the test cycle, acquires and processes the electrical sensor signals converting the signals into quantitative results. These functions are controlled by a microprocessor.

The i-STAT 1 System is comprised of the i-STAT 1 analyzer and accessories (i-STAT 1 Downloader/Recharger, i-STAT Electronic Simulator, i-STAT Printer and i-STAT 1 9V NiMH Rechargeable Battery).

Assay quality control materials are also available for use with the i-STAT hs-TnI cartridge and include i-STAT hs-TnI Control Level 1. i-STAT hs-TnI Control Level 2. i-STAT hs-TnI Control Level 3, and the i-STAT hs-TnI Calibration Verification Levels 1-3.

Acceptance Criteria and Device Performance for i-STAT hs-TnI Cartridge with i-STAT 1 System

This response outlines the acceptance criteria and the study that demonstrates the i-STAT hs-TnI Cartridge with the i-STAT 1 System meets these criteria, based on the provided FDA 510(k) summary.

1. Table of Acceptance Criteria and Reported Device Performance

The provided document doesn't explicitly list "acceptance criteria" in a single, consolidated table with pass/fail remarks. Instead, it presents performance characteristics and states whether the results "met the acceptance criteria" or "demonstrated acceptable performance." Based on this, the table below synthesizes the reported performance against inferred acceptance criteria.

Table: Acceptance Criteria and Reported Device Performance

2. Sample Sizes and Data Provenance

• Test Set Sample Size:

  • 20-Day Precision: 240 replicates per level for 6 plasma samples (total 1440 tests across 3 cartridge lots, 20 days).
  • Whole Blood and Plasma Precision: Min. 24 replicates per level (6 levels) per site (3 sites) for whole blood and plasma specimens. Total number of replicates for whole blood was 576, and for plasma was 576.
  • Precision in Control Materials: 25 replicates per level (5 levels) for control materials.
  • Multi-site Multi-Day Precision: 90 replicates per level (6 plasma samples) (total 540 tests across 3 sites, 5 days, 2 operators).
  • Linearity: Not explicitly stated as a single number but implied by samples covering the reportable range.
  • Sample Type Comparison (WB vs. Plasma): Not explicitly stated, implied by samples covering the reportable range.
  • High Dose Hook Effect: Not explicitly stated.
  • LoB/LoD: Not explicitly stated, but involved 4 healthy donors for each sample type and multiple cartridge lots.
  • LoQ: Not explicitly stated, but involved a low-level cTnI whole blood and plasma samples and 4 cartridge lots.
  • Interference: Tested at two cTnI levels using various interfering substances.
  • Cross-reactivity: Tested at three cTnI concentrations for each cross-reactive substance.
  • Hematocrit Sensitivity: Whole blood samples at two cTnI levels and seven hematocrit levels.
  • Altitude: Not explicitly stated as a single number but involved whole blood and plasma samples at relevant cTnI levels.
  • Matrix Equivalence (Non-Anticoagulated WB vs. Li-Heparin WB): 88 paired specimens (including 8 contrived).
  • Matrix Equivalence (Li-Heparin Tube with Separator Gel vs. Li-Heparin Tube): 87 paired specimens (including 8 contrived).
  • Clinical Sensitivity and Specificity: 3585 subjects presenting to the Emergency Department.

• Data Provenance:

  • Analytical Performance Studies (Precision, Linearity, Hook Effect, LoB/LoD/LoQ, Interference, Cross-reactivity, Hematocrit, Altitude): These studies used a combination of frozen plasma samples, native venous whole blood and plasma specimens (prospectively collected), whole blood/plasma samples altered via spiking, control materials, and healthy donor samples. The studies were conducted at various clinical sites and internally at Abbott Point of Care.
  • Reference Interval Study: United States (US) based general population, prospectively collected venous whole blood specimens from 895 apparently healthy subjects at 8 clinical sites.
  • Matrix Equivalence Studies: Prospectively collected venous whole blood and plasma specimens from patients in point of care settings at two (2) clinical sites.
  • Clinical Sensitivity and Specificity (Pivotal Study): Prospectively collected venous whole blood and plasma specimens at 28 clinical sites in the United States. These sites were geographically diverse EDs associated with acute care hospitals, medical centers, tertiary care facilities, and primary care clinics.

3. Number of Experts and Qualifications for Ground Truth

• Clinical Sensitivity and Specificity Study (Pivotal Study):

  • Number of Experts: Not explicitly stated as a specific number, but referred to as "board-certified cardiologists and/or emergency medicine physicians."
  • Qualifications: Board-certified cardiologists and/or emergency medicine physicians. No specific years of experience are detailed.
  • Role: Adjudicated subjects based on the fourth universal definition of MI.

• Other Studies: The document does not indicate the involvement of external experts for establishing ground truth for other analytical performance or matrix equivalence studies. Ground truth for these was established through standard laboratory methods, spiked samples, and reference materials.

4. Adjudication Method for the Test Set

• Clinical Sensitivity and Specificity Study: The adjudication method for the clinical study involved "adjudication by board-certified cardiologists and/or emergency medicine physicians based on the fourth universal definition of MI." The adjudicators were blinded to the i-STAT hs-TnI test results, indicating an independent review process. The specific number of adjudicators per case (e.g., 2+1, 3+1) is not provided, but the mention of plural "physicians" suggests at least two.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

• The document does not mention a multi-reader multi-case (MRMC) comparative effectiveness study to assess how much human readers improve with AI vs. without AI assistance. The device is an in vitro diagnostic test (IVD) for quantitative measurement of cTnI, not an imaging device or AI-powered diagnostic aide for human interpretation.

6. Standalone (Algorithm Only) Performance Study

• The performance studies described are inherently standalone for the device itself. The i-STAT hs-TnI cartridge with the i-STAT 1 System is a diagnostic test that provides a quantitative result. The clinical sensitivity and specificity are reported for the device's output (cTnI levels) as an aid in MI diagnosis, without human-in-the-loop interpretation of raw data from the device beyond reading the final numerical result.

7. Type of Ground Truth Used

• Clinical Sensitivity and Specificity Study: The ground truth for the diagnosis of MI was established by expert consensus (board-certified cardiologists and/or emergency medicine physicians) based on the fourth universal definition of MI. This is a clinical outcome/diagnostic ground truth.
• Analytical Studies:
  • Precision, Linearity, Hook Effect, LoB/LoD/LoQ, Interference, Cross-reactivity, Hematocrit, Altitude, Matrix Equivalence: Ground truth was established using a combination of:
    • Known concentrations in spiked samples.
    • Reference methods/materials (e.g., NIST SRM2921 for traceability).
    • Standard laboratory measurements and pre-defined expected values for linearity and comparison studies.
    • Clinical classification based on robust biomarker criteria (for the reference interval study of healthy subjects).

8. Sample Size for the Training Set

• The document describes performance evaluation studies and does not explicitly differentiate a "training set" for an AI/machine learning model. The i-STAT hs-TnI test is an immunoassay (ELISA method with electrochemical detection), not a device based on AI/ML. Therefore, the concept of a "training set" for an algorithm is not directly applicable in the context of this device description. The studies described are for analytical and clinical validation of the assay.

9. How the Ground Truth for the Training Set Was Established

• As stated in point 8, the device is an immunoassay, not an AI/ML system, so there isn't a "training set" in that conventional sense. The "ground truth" for the various analytical and clinical studies (which could be considered analogous to data used for establishing performance) was established as described in point 7.

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The Atellica® IM High-Sensitivity Troponin I (TnIH) assay is for in vitro diagnostic use in the quantitative measurement of cardiac troponin I in human serum or plasma (lithium heparin) using the Atellica® IM Analyzer. The assay can be used to aid in the diagnosis of acute myocardial infarction (AMI).

The Atellica IM TnIH assay can be used as an aid in prognosis for 30-, 182-, and 365-day all-cause mortality (ACM) and major adverse cardiac events (MACE) in patients presenting with signs and symptoms suggestive of acute coronary syndrome (ACS). MACE consists of myocardial infarction, urgent revascularization, cardiac death, or heart failure hospitalization.

The Atellica® IM TnIH assay is a 3-site sandwich immunoassay using direct chemiluminescent technology. The Solid Phase reagent consists of magnetic particles conjugated with streptavidin with 2 bound biotinylated capture monoclonal antibodies, each recognizing a unique cTnl epitope.

The Lite Reagent comprises a conjugate with an architecture consisting of a proprietary acridinium ester and a recombinant anti-human cTnl sheep Fab covalently attached to bovine serum albumin (BSA) for chemiluminescent detection.

A direct relationship exists between the amount of cTnl present in the patient sample and the amount of relative light units (RLUs) detected by the system.

The provided document is a 510(k) summary for the Atellica® IM High-Sensitivity Troponin I (TnIH) assay, detailing its substantial equivalence to a predicate device and supporting the addition of a prognostic indication for use. However, it does not explicitly define acceptance criteria as a separate, quantitative table with pass/fail metrics. Instead, the "Performance Characteristics – Clinical Study" section presents the study objective and results that demonstrate the device's performance for the new prognostic indication, implicitly serving as the validation for meeting the FDA's requirements for substantial equivalence.

Based on the information provided, here's a breakdown of the requested elements:

1. A table of acceptance criteria and the reported device performance

The document does not provide a formal table of acceptance criteria with quantitative thresholds for "pass/fail". The study's objective was to demonstrate the ability of the device to predict future mortality or adverse cardiac events. The reported performance focuses on:

• Hazard Ratios (Unadjusted and Adjusted): Showing the increased risk of ACM/MACE for patients with cTnI levels >99th percentile compared to those ≤99th percentile.
• Post-test risk: The cumulative incidence of ACM/MACE for the two troponin level groups.
• Kaplan-Meier Curves: Visually representing the absolute risk of events over time for the two groups.

The implicit acceptance criteria for this prognostic indication would be that the device's measurements (specifically, cTnI levels > 99th percentile) demonstrate a statistically significant association with increased future risk of all-cause mortality (ACM) and major adverse cardiac events (MACE) across the specified follow-up periods (30, 90, 182, and 365 days) in the relevant patient populations.

Reported Device Performance (Excerpted from the document, focusing on statistically significant findings):

Note: Bolded Hazard Ratios indicate statistically significant findings (95% CI does not cross 1.0). Italicized Hazard Ratios (e.g., serum at 30, 90, 365 days for Population 2) are explicitly marked as "Not Statistically Significant" in the document.

The overall conclusion states: "The results of the clinical study provided in this submission support the addition of an indication for use as an aid in prognosis for all-cause mortality (ACM) and major adverse cardiac events (MACE) in patients presenting with signs and symptoms suggestive of acute coronary syndrome (ACS)." This implies that the observed effects (higher risk for cTnI > 99th percentile) were deemed sufficient, particularly for the statistically significant findings.

2. Sample sized used for the test set and the data provenance (e.g., country of origin of the data, retrospective or prospective)

• Test Set Sample Size:
  • Population 1: 2064 patients
  • Population 2:
    • Lithium Heparin Plasma: 1190 patients
    • Serum: 1214 patients
  • Population 3: 874 patients
• Data Provenance: The document states, "This prognostic risk analysis utilized the same emergency department cohort previously described in K171566." It does not explicitly state the country of origin. The study was prospective in terms of follow-up for outcomes after initial presentation, as patients were "followed up for 30-, 90-, 182-, and 365-day progression to ACM and MACE."

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g., radiologist with 10 years of experience)

The ground truth for Adjudicated AMI was mentioned ("Entire Population Excluding Subjects with Adjudicated AMI"). The document does not specify the number or qualifications of experts used for establishing this adjudication or for the MACE/ACM outcomes. It says "a detailed symptom history was obtained for each subject" and "the following information was collected from each subject's medical chart." This suggests medical record review, but the specific adjudicators are not detailed.

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set

The document mentions "adjudicated AMI" and the collection of outcome data (ACM/MACE events). However, it does not describe the specific adjudication method (e.g., how many reviewers, conflict resolution) for AMI or the MACE/ACM outcomes. It implies that MACE consisted of clearly defined clinical events (myocardial infarction, urgent revascularization, cardiac death, or heart failure hospitalization) which are typically obtained from medical records.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

No. This is an in vitro diagnostic (IVD) assay for measuring a biomarker (Troponin I). It is not an AI-assisted imaging device or a device involving "human readers" in the typical sense of an MRMC study. The study assesses the prognostic performance of the cTnI assay result itself, not human interpretation enhanced by AI.

6. If a standalone (i.e., algorithm only without human-in-the loop performance) was done

Yes, in a sense. The performance evaluated is that of the assay (the Atellica® IM High-Sensitivity Troponin I (TnIH) measurement) as a standalone prognostic indicator, reported as a quantitative value. It's the "algorithm" of the assay (producing the cTnI value) that is assessed for its ability to predict outcomes in patient populations, without direct human cognitive input being part of the primary performance metric. Clinical decision-making would then incorporate this result.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

The ground truth for the prognostic indication was outcomes data, specifically:

• All-Cause Mortality (ACM)
• Major Adverse Cardiac Events (MACE): Consisting of myocardial infarction, urgent revascularization, cardiac death, or heart failure hospitalization.
  This long-term outcome data was collected from patient follow-up over 30, 90, 182, and 365 days.

8. The sample size for the training set

The document describes a clinical performance study for the new prognostic indication. It does not mention a separate "training set" for model development, implying that this was a single-cohort validation study using the full collected dataset (the test set described above). The purpose of the submission is to expand the intended use of an already existing device (cleared under K171566), suggesting the core assay technology was already established.

9. How the ground truth for the training set was established

As no separate "training set" is explicitly mentioned for the prognostic model development (if one occurred), this question is not fully answerable from the provided text. The ground truth for the clinical validation (the "test set") was established through prospective follow-up for clinical outcomes (ACM/MACE) as described in point 7.

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PATHFAST® hs-cTnl-II is an in vitro diagnostic test for the quantitative measurement of cardiac Troponin I (cTnl) in heparinized or EDTA whole blood and plasma. Measurements of cardiac Troponin I are used as an aid in the diagnosis of acute myocardial infarction (AMI). PATHFAST® hs-cTnI-II is for use in clinical laboratory or point of care (POC) settings.

The PATHFAST® hs-cTnI-II test is a chemiluminescent enzyme immunoassay performed on the PATHFAST® instrument. Patient samples, whole blood or plasma, are dispensed by the operator into the designated area on the reagent cartridge. The instrument combines the patient sample, the antibody coated magnetic particles, and the alkaline phosphatase conjugate and incubates the mixture for 5 minutes at 37℃. During this incubation, the analyte in the patient sample binds to the antibody on the coated particles, and the alkaline phosphatase conjugate binds to the analyteantibody coated-particle. After the incubation, the instrument performs Bound/Free (B/F) separation using Magtration® technology to remove any excess unbound reagents. The chemiluminescent substrate is then added. The substrate is catalyzed by the bound alkaline phosphatase, which results in emission of photons. The photo-multiplier tube in the PATHFAST® instrument detects the photons that are emitted during the reaction. The chemiluminescent count is converted to analyte concentration values by the instrument based on the master calibration curve for the reagent lot. The PATHFAST® hs-cTnI-II test is supplied in reagent kits. Each kit contains sufficient materials for 60 determinations. The calibrator materials are included with the reagent kit and are also available separately. Calibration kits and diluent kits are also provided separately.

The provided text describes the regulatory clearance of the PATHFAST® hs-cTnI-II device, a diagnostic test for cardiac Troponin I (cTnI), and its comparison to a legally marketed predicate device (PATHFAST® cTnI-II, K100130). The focus of this document is on the analytical performance and how modifications to the reporting range do not affect clinical performance, relying on data from the predicate device.

Here's a breakdown of the requested information based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

For this device, the "acceptance criteria" are tied to its analytical performance and how it meets the claims for its intended use, especially concerning linearity, detection limits, and maintaining the clinical significance established by the predicate.

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Access hsTnI is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of cardiac troponin I (cTnl) levels in human serum and plasma using the DxI Access Immunoassay Analyzers to aid in the diagnosis of myocardial infarction (MI).

The Access hsTnl assay is a sandwich immunoenzymatic assay. The Access hsTnl assay consists of the reagent pack and calibrators. Other items needed to run the assay include substrate and wash buffer. The Access hsTnl reagent pack, Access hsTnl calibrators, along with the UniCel Dxl Wash Buffer II are designed for use with the Dxl 9000 Access Immunoassay Analyzer in a clinical laboratory setting.

The provided text describes the Beckman Coulter Access hsTnI device, a chemiluminescent immunoassay for the quantitative determination of cardiac troponin I (cTnI) to aid in the diagnosis of myocardial infarction (MI). The information below summarizes the acceptance criteria and the study used to prove the device meets these criteria.

1. A table of acceptance criteria and the reported device performance

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Access hsTnI is a paramagnetic particle, chemiluminescent immunoassay for the quantitative determination of cardiac troponin I (cTnl) levels in human serum and plasma using the Access 2 Immunoassay Systems to aid in the diagnosis of myocardial infarction (MI).

The Access hsTnI is a two-site immunoenzymatic ("sandwich") assay. Monoclonal anti-cTnl antibody coniugated to alkaline phosphatase is added to a reaction vessel along with a surfactant-containing buffer and sample. After a short incubation, paramagnetic particles coated with monoclonal anti-cTnl antibody are added. The human cTnl binds to the anti-cTnl antibody on the solid phase, while the anti-cTnl antibody-alkaline phosphatase conjugate reacts with different antigenic sites on the cTnl molecules. After incubation, materials bound to the solid phase are held in a magnetic field while unbound materials are washed away. Then, the chemiluminescent substrate is added to the vessel and light generated by the reaction is measured with a luminometer. The light production is directly proportional to the concentration of analyte in the sample. Analyte concentration is automatically determined from a stored calibration.

Here's a breakdown of the acceptance criteria and study details for the Access hsTnI device, based on the provided FDA 510(k) summary:

1. Table of Acceptance Criteria and Reported Device Performance

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The Alinity i STAT High Sensitivity Troponin-I assay is a chemiluminescent microparticle immunoassay (CMIA) used for the quantitative determination of cardiac troponin I (cTnl) in human plasma (lithium heparin) on the Alinity is ystem.

The Alinity i STAT High Sensitivity Troponin-I assay is to be used as an aid in the diagnosis of myocardial infarction (MI).

The Alinity i STAT High Sensitivity Troponin-I Reagent Kit contains:

• . Microparticles: 1 bottle (6.6 mL per 100 test cartridge / 33.8 mL per 600 test cartridge). Anti-troponin I (mouse, monoclonal) coated microparticles in TRIS buffer with protein (bovine) stabilizer. Minimum concentration: 0.035% solids. Preservative: ProClin 300.
• . Conjugate: 1 bottle (6.1 mL per 100 test cartridge / 33.8 mL per 600 test cartridge). Anti-troponin I (mouse-human chimeric, monoclonal) acridinium-labeled conjugate in MES buffer with protein (bovine) stabilizer and human IgG. Minimum concentration: 0.1 mg/L. Preservative: ProClin 300.

The Alinity i STAT High Sensitivity Troponin-I device is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of cardiac troponin I (cTnI) in human plasma (lithium heparin) on the Alinity i system, used as an aid in the diagnosis of myocardial infarction (MI).

The acceptance criteria and device performance are as follows:

1. Table of Acceptance Criteria and Reported Device Performance

2. Sample Size Used for the Test Set and Data Provenance

• Dilution Recovery Study: Samples were prepared by volumetrically spiking lithium heparin plasma with purified recombinant human cardiac troponin IC complex.
  • Automated Dilution: Each sample was tested in replicates of 5. The total number of unique samples is not explicitly stated, but implies multiple samples across a range up to 60,000.0 ng/L.
  • Manual Dilution: The same samples were used, and each dilution was prepared by 2 technicians and tested. Again, the exact number of unique samples is not stated but implies multiple samples.
• Data Provenance: The document does not specify the country of origin for the data. The study appears to be prospective laboratory testing conducted to evaluate the device's performance characteristics.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of those Experts

Not applicable. This device is an in vitro diagnostic immunoassay, and the "ground truth" for the dilution recovery study was established by the known concentration of spiked cTnI in the plasma samples, rather than expert interpretation of images or clinical cases.

4. Adjudication Method for the Test Set

Not applicable. Given the nature of the dilution recovery study for an immunoassay, an adjudication method for establishing ground truth as typically understood in AI/imaging studies (e.g., 2+1, 3+1) is not relevant. The "ground truth" for recovery was the known spiked concentration.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study was done

No, a Multi Reader Multi Case (MRMC) comparative effectiveness study was not done. This device is an in vitro diagnostic immunoassay; therefore, human reader performance or the improvement with AI assistance is not applicable.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done

Yes, the performance testing for dilution recovery was conducted as a standalone algorithm performance without human-in-the-loop performance. The Alinity i system automatically processes samples and measures relative light units to quantify cTnI. The study evaluated the accuracy of dilution performed by the instrument and manually.

7. The Type of Ground Truth Used

The ground truth for the dilution recovery study was known, spiked concentrations of purified recombinant human cardiac troponin IC complex in lithium heparin plasma. This represents an analytical ground truth based on controlled experimental conditions.

8. The Sample Size for the Training Set

The document does not provide information about a training set since this is not an AI/machine learning device that typically requires a large training set. The "subject device" is an immunoassay system, and its performance is evaluated based on its analytical characteristics.

9. How the Ground Truth for the Training Set Was Established

Not applicable, as there is no mention or indication of a "training set" for this in vitro diagnostic immunoassay.

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The Alinity i STAT High Sensitivity Troponin-I assay is a chemiluminescent microparticle immunoassay (CMIA) used for the quantitative determination of cardiac troponin I (cTnI) in human plasma (lithium heparin) on the Alinity i system.

The Alinity i STAT High Sensitivity Troponin-I assay is to be used as an aid in the diagnosis of myocardial infarction (MI).

The Alinity i STAT High Sensitivity Troponin-I Reagent Kit contains:

• . Microparticles: 1 bottle (6.6 mL per 100 test cartridge / 33.8 mL per 600 test cartridge). Anti-troponin I (mouse, monoclonal) coated microparticles in TRIS buffer with protein (bovine) stabilizer. Minimum concentration: 0.035% solids. Preservative: ProClin 300.
• . Conjugate: 1 bottle (6.1 mL per 100 test cartridge / 33.8 mL per 600 test cartridge). Anti-troponin I (mouse-human chimeric, monoclonal) acridinium-labeled conjugate in MES buffer with protein (bovine) stabilizer and human IgG. Minimum concentration: 0.1 mg/L. Preservative: ProClin 300.

The Alinity i STAT High Sensitivity Troponin-I assay is an automated, two-step immunoassay for the quantitative determination of cTnI in human plasma (lithium heparin) using CMIA technology.

Sample and anti-troponin I antibody-coated paramagnetic microparticles are combined and incubated. The cTnI present in the sample binds to the anti-troponin I coated microparticles. The mixture is washed. Anti-troponin I acridinium-labeled conjugate is added to create a reaction mixture and incubated. Following a wash cycle, Pre-Trigger and Trigger Solutions are added. The resulting chemiluminescent reaction is measured as a relative light unit (RLU). There is a direct relationship between the amount of cTnI in the sample and the RLU detected by the system optics.

Acceptance Criteria and Study for Alinity i STAT High Sensitivity Troponin-I

1. Table of Acceptance Criteria and Reported Device Performance:

The document does not explicitly state formal acceptance criteria in a tabular format for the clinical performance. However, typical performance metrics for diagnostic assays like this include:

• Sensitivity: 85.29% to 98.46% (Female), 72.20% to 92.06% (Male) depending on time point.
• Specificity: 69.13% to 85.64% (Female), 74.22% to 88.98% (Male).
• PPV: 27.02% to 42.74% (Female), 33.78% to 50.00% (Male).
• NPV: 98.80% to 99.85% (Female), 97.05% to 99.19% (Male).

Overall cutoff (27 ng/L):

• Sensitivity: 78.43% to 94.44% (Female), 76.45% to 94.44% (Male)
• Specificity: 66.44% to 92.57% (Female), 66.44% to 88.34% (Male).
• PPV: 35.09% to 47.66% (Female), 29.06% to 44.07% (Male).
• NPV: 98.37% to 99.46% (Female), 97.40% to 99.35% (Male). | The high NPV across all time points and cutoffs is a strong indicator of the assay's ability to rule out MI. Sensitivities are also generally high. The lower PPV reflects the prevalence of non-MI conditions that can elevate troponin and emphasizes the need for combining results with clinical data. The study notes that lower specificity at ≥6 hours is due to study design and patient flow in the ED. |
  | AUC | Not explicitly stated as an acceptance criterion, but higher values indicate better diagnostic performance. Generally, AUC > 0.9 is considered excellent. | AUC: 0.9257 to 0.9777 (Female), 0.8994 to 0.9489 (Male) across different time points. | Consistently high AUC values, indicating excellent overall diagnostic accuracy for both sexes and at different time points. |

Study Proving Acceptance Criteria:

The study described is a multi-center prospective clinical study designed to assess the diagnostic accuracy of the Alinity i STAT High Sensitivity Troponin-I assay in patients presenting with chest discomfort or equivalent ischemic symptoms.

2. Sample size used for the test set and the data provenance:

• Sample Size (Clinical Study):
  • Total Subjects: 6174
  • MI Subjects: 432 (124 female, 308 male)
  • Non-MI Subjects: 5742 (2128 female, 3614 male)
  • Total Specimens (serial sampling):
    • 891 from MI subjects
    • 8975 from non-MI subjects
• Data Provenance:
  • Country of Origin: United States (implied by the FDA 510(k) submission context for a US population reference range study). The study was conducted at 23 Emergency Departments (EDs) in the US, reflecting regional, urban, and rural patient populations.
  • Retrospective or Prospective: Prospective. Specimens were collected prospectively from subjects presenting to the ED.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

• Number of Experts: A "panel of board-certified cardiologists" was used. The exact number is not explicitly stated, but "panel" implies more than one.
• Qualifications of Experts: Board-certified cardiologists.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set:

• Adjudication Method: The subject diagnoses (MI or non-MI) were adjudicated by a panel of board-certified cardiologists based on the third universal definition of MI. The adjudicators were blinded to the Alinity i STAT High Sensitivity Troponin-I assay results. This indicates an expert consensus method, likely involving all panel members reaching a decision, but the specific voting scheme (e.g., 2+1, 3+1) is not detailed.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

• No, a MRMC comparative effectiveness study was not done. This document describes the performance of a lab assay (IVD - In Vitro Diagnostic), not an AI-assisted diagnostic tool that would typically involve human readers.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:

• Yes, a standalone performance study was done. The entire clinical study described assesses the performance of the Alinity i STAT High Sensitivity Troponin-I assay (the "algorithm" or device in this context) as a standalone diagnostic tool for aid in MI diagnosis. The results (sensitivity, specificity, PPV, NPV, AUC) are presented for the direct output of the assay. The wording "aid in the diagnosis" implies it's used in conjunction with other clinical information, but its individual performance is what's being evaluated.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc):

• Expert Consensus and Clinical Definition: The ground truth for MI diagnosis was established by a panel of board-certified cardiologists based on the third universal definition of MI. This definition incorporates clinical observations, ECG, and other diagnostic information, which can include pathology and outcomes data indirectly but is primarily an expert consensus application of a standardized clinical definition.

8. The sample size for the training set:

• Not Applicable / Not Explicitly Stated for the Clinical Study. This document describes an IVD device, not an AI/machine learning model in the traditional sense that requires an explicit "training set" of patient data for model development. The "training" for such an assay involves the optimization of reagents, antibodies, and detection protocols during product development. The non-clinical studies (precision, linearity, interference) represent the internal testing and validation that inform the assay's operational parameters. The clinical study described functions as a validation/test set for the final device performance.

9. How the ground truth for the training set was established:

• Not Applicable. As noted above, for this IVD device, there isn't a "training set" of patient data with ground truth in the way there is for AI/ML algorithms. The ground truth for the assay's development and calibration would typically be established using manufactured controls, calibrators, and characterized reference materials with known concentrations of cTnI, following industry standards and guidelines (e.g., CLSI documents referenced in the non-clinical section).

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Immunoassay for the in vitro quantitative determination of cardiac troponin T (cTnT) in lithium heparin plasma. The immunoassay is intended to aid in the diagnosis of myocardial infarction.

The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

The Elecsys Troponin T Gen 5 STAT Immunoassay is a one-step sandwich immunoassay on the cobas e 601 and cobas e 801 analyzer. The assay uses streptavidin-coated microparticles, a biotinylated monoclonal anti-cardiac Troponin T-specific antibody, a monoclonal anti-cardiac Troponin T-specific antibody labeled with a ruthenium complex and electrochemiluminescence detection. Results are determined using a calibration curve that is generated specifically on each instrument by a 2-point calibration and a master curve (6-point calibration) provided with the reagent bar code.

Here's an analysis of the acceptance criteria and supporting study for the Elecsys Troponin T Gen 5 device, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document primarily focuses on demonstrating substantial equivalence to a predicate device rather than explicitly stating individual acceptance criteria for each analytical performance metric. However, for some metrics, "predetermined acceptance criterion" is mentioned. I will extract those with stated criteria and their outcomes.

2. Sample Size Used for the Test Set and Data Provenance

• Analytical Performance Studies (Precision, LoB, LoD, LoQ, Linearity, Interference, Cross-Reactivity):

  • Sample Types: Human Li-Heparin plasma samples (native, pooled, or spiked with recombinant Troponin T).
  • Provenance: Not explicitly stated for specific samples, but implied to be from internal or external sites where the tests were conducted (e.g., "one internal site," "three different sites (one internal and two external sites)"). These are typically retrospective samples used for method validation.
  • Sample Sizes (examples):
    • Precision (Repeatability/Intermediate): Six human samples (sample pools) for 21 days with two replicates/day (4 replicates total per day for 21 days). Total 6 samples * 4 replicates/day * 21 days = 504 measurements per sample material.
    • Precision (Reproducibility): Five human Li-Heparin plasma samples and two controls, measured five-fold for 5 days on three analyzers at three sites. Total 7 materials * 5 replicates * 5 days * 3 sites = 525 measurements across all sites.
    • LoB: One analyte-free Li-Heparin plasma sample, measured in ten-fold determinations in each of six runs over at least three days. Total 60 measurements.
    • LoD: Five low-analyte Li-Heparin plasma samples, measured in two-fold determination, six runs over at least three days. Total 60 determinations per reagent lot (so 180 for 3 lots).
    • LoQ: Ten native Li-Heparin plasma pools and two controls, collected over 21 days with two runs per day. Total 12 materials * 2 runs/day * 21 days = 504 runs, with variance components calculated from these.
    • Linearity: Three high analyte Li-Heparin plasma samples diluted with three low analyte samples to generate at least sixteen concentrations (15 dilutions). Assayed in 3-fold determinations within a single run.
    • HAMA/Endogenous Interference: Two samples with low cTnT spiked with HAMA (in duplicate); Three native Li-Heparin plasma samples (low, medium, high cTnT) for endogenous interferents (3-fold determination).
    • Cross-Reactivity: Three concentrations of troponin samples spiked with four different cross-reactants, tested in three-fold determination.
    • Exogenous Interference (Drugs): Native Li-Heparin plasma samples spiked with 17 common pharmaceutical compounds and 22 cardiac drugs (3-fold determination).

• Clinical Performance Studies (APACE Trial and second multicenter study):

  • APACE Trial:
    • N: 1074 subjects enrolled, 3023 available samples. 188 adjudicated diagnoses of MI.
    • Provenance: International, multicenter prospective trial.
  • Second Multicenter Study:
    • N: 1679 subjects presenting emergently with chest pain were enrolled. 173 adjudicated MIs. 1675 subjects evaluated on the cobas e 601 analyzer.
    • Provenance: Multicenter study (locations not specified, but typically clinical sites).

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications

• APACE Trial: "Independent adjudication committee which included cardiologists."
• Second Multicenter Study: "Independent adjudication committee which included cardiologists and emergency medicine physicians."
• Qualifications: "Cardiologists" and "emergency medicine physicians" are the stated qualifications. Specific years of experience are not provided.

4. Adjudication Method for the Test Set

• APACE Trial: "In the case of a disagreement, a third independent cardiologist was used as the tie breaker." This describes a 2+1 or 3-way consensus adjudication method.
• Second Multicenter Study: "Final diagnoses were determined by an independent adjudication committee... using the universal guidelines." The specific tie-breaking method is not explicitly stated, but implies a consensus process.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

• No, an MRMC comparative effectiveness study was not done. The document describes a method comparison study (comparing the candidate device to a predicate device) and clinical performance studies (diagnostic sensitivity/specificity of the device against a clinical ground truth).
• There is no mention of human readers' performance with and without AI assistance, nor is there an effect size for human improvement with AI. This is an in vitro diagnostic device, not a diagnostic imaging AI algorithm that would typically involve human reader studies.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance)

• Yes, this is a standalone performance study. The Elecsys Troponin T Gen 5 immunoassay is an in vitro diagnostic device that provides quantitative measurements of cardiac troponin T (cTnT). Its performance (analytical and clinical) is evaluated against established methods and clinical endpoints, independent of real-time human interpretation or intervention in the measurement process itself. The "human-in-the-loop" would be the clinician interpreting the result, but the device's measurement itself is standalone.

7. Type of Ground Truth Used

• Clinical Performance Studies (APACE Trial & second multicenter study):

  • Adjudicated Clinical Diagnosis of Myocardial Infarction (MI). This ground truth was established by an independent adjudication committee (cardiologists, sometimes with emergency medicine physicians) using established diagnostic criteria (e.g., ACC/ESC/AHA guidelines, including ECG changes, symptoms, and elevation of cardiac troponin). For the APACE trial, 60-day follow-up information was also used.

• Analytical Performance Studies:

  • For most analytical studies like precision, LoB, LoD, LoQ, linearity, and interference, the ground truth is often defined by:
    • Reference materials/standards: For calibration and standardization.
    • Known concentrations: For spiked samples and dilution series.
    • Analyte-free samples: For LoB determination.
    • Predicate device results: For method comparison studies. This isn't strictly "ground truth" but a reference for comparative equivalence.

8. Sample Size for the Training Set

• The document describes a measurement device (immunoassay), not an AI/ML algorithm that is "trained" in the conventional sense on a dataset. Therefore, there isn't a "training set" in the context of an AI algorithm learning from data.
• The device's calibration and standardization, however, rely on specific procedures:
  • Calibration Curve: Generated specifically on each instrument by a 2-point calibration and a master curve (6-point calibration) provided with the reagent bar code. This essentially "calibrates" the device to provide accurate quantitative results.
  • Standardization: Against Elecsys Troponin T STAT assay (4th generation), which in turn was standardized against the Enzymun-Test Troponin T (CARDIAC T) method. This refers to the traceable method of establishing the quantitative scale.

9. How the Ground Truth for the Training Set Was Established
As noted in point 8, this device does not utilize a "training set" in the context of AI/ML. Its operational "ground truth" or reference for quantitative measurement is established through:

• Known Calibrator Values: The master curve calibration relies on calibrators with accurately assigned values, which are traceable back to a primary reference method (Enzymun-Test Troponin T, and further through the 4th generation assay).
• Analytical Validation Studies: The various analytical studies (precision, linearity, LoB, LoD, LoQ) are validation steps to ensure the device accurately measures cTnT across its intended range, rather than a "training" phase. These studies confirm the device's ability to consistently provide results that align with expected or known values.

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